Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats.
OBJECTIVE
Mesenchymal stem cells (MSCs) may modulate inflammatory responses resulting in improvement in inflammatory diseases, as well as tissue regeneration via cellular differentiation. We examined the therapeutic effects of exogenously administered MSCs in dextran sulfate sodium (DSS)-induced colitis in rats.


METHODS
Experimental colitis was produced in inbred male Lewis rats by administration of 4% DSS in drinking water for 7 days. MSCs (5x10(6) cells) which were isolated from whole marrow cells and cultured in an optimal medium for MSC outgrowth were administered to the treated rats via the tail vein on days 0, 2, and 4. On day 7, we evaluated colon length, histological changes, and colonic various mRNA expressions by RT-PCR. Localization of MSCs was evaluated using a green-fluorescent cell linker dye. To evaluate the anti-inflammatory action of MSCs, we assayed LPS-induced TNF-alpha secretion in a co-culture of MSCs and monocytes (THP-1 cells) using ELISA.


RESULTS
MSCs reduced in bloody stools, weight loss, colon shortening, and microscopic injuries. In the rectum of MSCs-treated rats, mRNA expression of TNF-alpha, IL-1beta, and COX-2 decreased to 40, 15, and 15% of their respective control levels. MSCs significantly suppressed mRNA expression of VEGF, HGF, and b-FGF to 40, 25, and 25% of their respective control levels. Green-fluorescent-labeled MSCs were found only within the lamina propria in inflamed regions. LPS-induced TNF-alpha secretion by THP-1 cells was significantly suppressed by co-culture with MSCs dose-dependently.


CONCLUSIONS
We conclude that exogenous MSCs accumulated in inflamed tissues and ameliorated DSS-induced colitis via a local anti-inflammatory action.
Tanaka
Fumio
F
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Tominaga
Kazunari
K
Ochi
Masahiro
M
Tanigawa
Tetsuya
T
Watanabe
Toshio
T
Fujiwara
Yasuhiro
Y
Ohta
Kensuke
K
Oshitani
Nobuhide
N
Higuchi
Kazuhide
K
Arakawa
Tetsuo
T
D000208:Acute Disease; D000818:Animals; D002454:Cell Differentiation; D003092:Colitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000276:immunology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D018836:Inflammation Mediators / Q000276:immunology*; D007375:Interleukin-1 / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology; D009000:Monocytes / Q000276:immunology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000276:immunology
D018836:Inflammation Mediators; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D016264:Dextran Sulfate; D051546:Cyclooxygenase 2